Women tended to lose more weight than men after taking weight-loss drugs for about a year, in an analysis of gender differences in clinical trials of these agents.

For example, in the Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1) clinical trial of semaglutide (Wegovy, Novo Nordisk), on average, women lost about 18% of their initial weight, whereas men lost 13% of their initial weight after 68 weeks of this pharmacotherapy.

This finding contrasts with most diet and/or physical activity regimens where men tend to lose more weight than women, the researchers report.

The study by Alyssa Susanto, PhD, and colleagues, was presented during an oral session at the International Congress on Obesity (ICO) 2022 in Melbourne, Australia.

Why Does Gender Affect Weight-Loss Outcomes?

“Most pharmacological interventions do not report weight loss separately for males and females, despite the established physiological and biological differences between genders,” note the researchers, from the Faculty of Medicine and Health at the University of Sydney, Australia.

They performed an initial analysis of phase 3 trials of semaglutide, liraglutide (Saxenda, Novo Nordisk), and sibutramine (Meridia, Abbott, which was withdrawn from market in 2010 due to cardiovascular adverse effects).

The results suggest that “outcomes from weight-loss trials should be reported for females and males separately,” Susanto told Medscape Medical News in an email.

Ultimately, “greater understanding of differences in responses to [weight-loss] interventions based on gender will allow treatments to be tailored for males and females to optimize [weight-loss] outcomes,” she said.

“It is interesting to note the gender differences in responses to both dietary/lifestyle and pharmacological interventions,” John Wilding, DM, past president of the World Obesity Federation, who was not involved with this study but was lead author of the STEP-1 trial, observed in a press release from the ICO.

“One possible explanation for the greater response in females to pharmacological interventions,” he continued, “may be that as (in general) women are lighter than men, and, when the drug doses are the same, this could result in women receiving slightly higher doses in relation to their body weight and therefore having a greater response to the drug,” said Wilding, professor of medicine, Aintree University Hospital, University of Liverpool, UK.

“It is more difficult to explain why men may do better in response to lifestyle interventions,” he added,” but this might relate to social factors and differences between men and women who choose to take part in research trials,” he suggested.

“Physiological variations between genders often result in [pharmacokinetic] differences in the way drugs are absorbed, handled, distributed, and excreted,” which might explain some of the study findings, said co-author Samantha Hocking, MD, PhD, an endocrinologist at Royal Prince Alfred Hospital and a clinical academic at the University of Sydney.

“Since females tend to be smaller than males, at the same dose of the drug, females receive a higher exposure, and higher exposure is usually related to greater weight loss,” Susanto added. “However, it is interesting that even at similar exposures of liraglutide, females still lost more weight than males.”

Men Tend to Lose More Weight Than Women With Lifestyle Changes

The currently approved weight-loss drugs in Australia are liraglutide, naltrexone/bupropion (Contrave, Currax), orlistat (Xenical, GlaxoSmithKline), phentermine (Duromine, iNova; Metermine, iNova; Phentermine Juno, Juno), and semaglutide, Susanto noted.

Previous studies have reported that men tended to lose more weight than women with nonpharmacologic (lifestyle) interventions for weight loss, including low-carbohydrate diets (Susanto et al, 2022), low-fat diets (Shai et al, 2008), Mediterranean diets (Susanto et al, under review), very-low-energy diets (Christensen et al, 2018), and exercise interventions (Donnelly and Smith, 2005), Susanto reported.

A systematic review (Williams et al, 2014) found that men lost more weight than women in 10 out of 11 studies of weight loss using diet and/or exercise.

But it was not clear if there were gender differences with weight-loss drugs.

The researchers searched for published articles as well as abstracts presented at conferences of phase 3 clinical trials of weight-loss drugs that had separate data for men and women.

They initially identified three trials:

• STEP-1: Once-Weekly Semaglutide in Adults with Overweight or Obesity, published in 2021 in the New England Journal of Medicine. This was a trial of 1961 participants with overweight or obesity, without diabetes but with at least one weight-related comorbidity (eg, hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease) randomized to semaglutide versus placebo for 68 weeks.

• SCOUT: Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects, published in 2010 in the New England Journal of Medicine. This was a trial of 10,744 adults age 55 or older with overweight or obesity with cardiovascular disease and/or diabetes but with at least one weight-related comorbidity randomized to sibutramine vs placebo for 12 months.

• SCALE: A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management, published in 2015 in the New England Journal of Medicine. This was a trial of 3723 adults with overweight or obesity without diabetes randomized to liraglutide vs placebo.

The main weight-loss results by gender were:

• STEP-1:

  • Mean change in weight after 68 weeks of semaglutide, in men vs women: –12.9% vs –18.4%, P < .05

  • Mean change in weight after 68 weeks of placebo, in men vs women: –3.5% vs –2.1%, P = .25

• SCOUT:

  • Mean change in weight after 12 months of sibutramine, in men vs women: –4.0% vs –5.2%, P < .0001

  • Mean change in weight after 12 months of placebo, in men vs women –1.9% vs –2.2%, P < .005

  • SCALE:

    • At the same exposure levels, women lost more weight than men.

    The researchers subsequently analyzed data from the STEP 2 and STEP 6 trials of semaglutide, the CONQUER trial of phentermine and topiramate (Qsymia, Vivus), and the SCALE Diabetes trial of liraglutide, which showed similar gender differences in responses to weight-loss drugs, as seen in the other three trials.

    Susanto has reported no relevant financial relationships. Hocking has reported serving on advisory boards and receiving honoraria and research support from Novo Nordisk. Wilding has reported receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to the University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to the University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation.

    International Congress on Obesity Medicine. Abstract 078. Presented October 19, 2022.  

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